HIV-associated neurocognitive disorder (HAND) is a multifactorial disease with inflammation and immune activation as prominent features that remain post-HAART. There is a critical need to identify key host factors and understand their molecular mechanisms of action contributing to HAND. Macrophages play a central role in the development of HAND. Our long-term goals are to identify key cellular pathways at the immune/CNS axis that modulate HIV-macrophage interactions which negatively impact neuronal function leading to the development of HAND. Osteopontin (OPN) is a multifunctional cytokine-like, secreted glycophosphoprotein whose over-expression in brain, cerebral spinal fluid (CSF) and plasma, is associated with neurodegenerative diseases including in non-human primate models of HIV. However, no direct link of OPN to neuronal degeneration in HAND has yet been established. We identified OPN as an upregulated gene in HIV-infected macrophages. Knockdown of OPN in macrophages significantly decreases HIV replication suggesting the novel finding that OPN plays a positive role in the viral life cycle. Similar to another study, we found significantly elevated OPN levels n the CSF of HIV-infected persons with severe cognitive disorder compared to CSF from mildly demented and HIV negative control subjects. OPN was also significantly increased in brain tissue extracts from HIV-infected patients with cognitive disorder compared to unimpaired subjects. We believe that OPN, through its ability to increase monocyte recruitment into the CNS and to stimulate specific cytokine/chemokine and inflammatory pathways, plays a central role in the development of HAND. Importantly, these OPN-mediated pathways could provide new potential therapeutic targets. Our central hypothesis is that over-expression of OPN from macrophages is a host response to HIV infection that acts as a feedback loop stimulating further macrophage activation that triggers processes leading to neuronal injury and dysfunction. Two aims will test and examine this hypothesis: 1) To determine whether OPN expression is associated with neuronal degeneration in HAND and 2) To identify the molecular mechanisms by which OPN modulates HIV-1 replication. PUBLIC HEALTH RELEVANCE: Despite anti-HIV therapy, the prevalence of mild or asymptomatic neurocognitive dysfunction (HAND) continues to increase as patients live longer. There is a critical need to identify and understand the molecular mechanisms of action of key mediators of HAND. This proposal will explore the role of osteopontin in HAND and as an activator of HIV replication in macrophages. Knowledge gained from this proposal will lead to the identification of cellular pathways for potential therapeutic targets.